DESCRIPTION: HIV protease inhibitors (PIs) represent successful therapy for HIV infection. We have recently determined, however, that patients treated with one or more of the inhibitors experience substantial decrease in bone mineral density. Of those, patients having undergone bone biopsy, the majority exhibit changes similar to type II (senile osteoporosis) in which remodeling is suppressed and both osteoblast and osteoclast (OC) recruitment and function are attenuated. We find that one PI, Ritonavir, decreases both OC formation and function. Since OCs initiate the remodeling cycle, this observation is consistent with the low bone turnover (remodeling) exhibited by patients treated with these drugs. Thus, understanding the mechanisms by which Ritonavir suppresses OC activity will provide the basis for normalizing bone remodeling in PI treated patients. OC precursors, cells in the myeloid lineage, when exposed to RANK-L, undergo a cell-type specific differentiation program resulting in the formation of multinucleated bone resorbing cells. RANK-L signals by binding to its receptor RANK, thus initiating a differentiation program and enhancing the resorptive activity of mature OCs. RANK signal transduction activates Nuclear Factor kappaB (NFkB), a family of transcription factors critical for OC formation. Based on the above facts we hypothesize that: Ritonavir, by blunting RANK-mediated differentiation, inhibits OC formation and function. Thus, our specific aim is to determine the mechanisms by which Ritonavir inhibits OC differentiation and function.